Fluticasone propionate I, chemically known as S-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate, is a member of the corticosteroidal androstane 17β-thioic acid fluoromethyl ester family and a synthetic steroid of the glucocorticoid family. The naturally occurring hormone, cortisol or hydrocortisone, is produced by the adrenal glands. Glucocorticoid steroids have potent anti-inflammatory actions. When used as a nasal inhaler or spray, the medication goes directly to the inside lining of the nose and very little is absorbed into the rest of the body.
Processes for the synthesis of fluticasone propionate I are known in the prior art, but are associated with various difficulties. For instance, the process disclosed in U.S. Pat. No. 4,335,121, a product patent assigned to Glaxo, starts with flumethasone, where barring the functional groups on C-17 all other required structural features are already in place. The functionalisation of C-17 is achieved by the sequence depicted in scheme 1.

The first step involved the oxidative cleavage of the hydroxymethyl group on C-17 in flumethasone, which is chemically known as 6α,9α-difluoro-11β,17α,21-trihydroxy-16α-methyl-androsta-1,4-diene-3,20-dione, by periodic acid to obtain 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-androsta-1,4-diene-3-one-17β-carboxylic acid 2. Activation of the carboxyl group of compound 2 using N,N′-carbonyldiimidazole (CDI) in dimethylformamide (DMF) and subsequent treatment with H2S gave 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid 3. The C-17 hydroxyl group of compound 3 was esterified using propionyl chloride and triethylamine (TEA) to obtain 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioic acid 4. Alkylation of compound 4 with bromochloromethane using NaHCO3 and dimethylacetamide (DMAc) gave S-chloromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate 5. Halogen exchange with NaI in acetone converted chloromethyl ester 5 into S-iodomethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate 6. In the final step, iodomethyl ester 6 was reacted with silver fluoride (AgF) in acetonitrile to obtain fluticasone propionate I. The chloromethyl ester 5 can also be converted into compound II with X═Br (S-bromomethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate) by using an appropriate nucleophile, such as lithium bromide.
Even though the process described above is eco-friendly, it is not capable of providing fluticasone propionate I sufficiently pure to meet the limits of stringent pharmacopoeial specifications (EP/USP), and the processing conditions for the conversion of chloromethyl ester 5 to iodomethyl ester 6 and then to fluticasone propionate I are very tedious and inefficient.
Specifically, the conversion of chloromethyl ester 5 to iodomethyl ester 6 disclosed in U.S. Pat. No. 4,335,121 suffers from following limitations:                Traces of chloromethyl ester 5 starting material remain even after long reaction times (more than 48 hours). These traces are carried through to subsequent stages up to fluticasone propionate I. The traces of chloromethyl ester 5 are difficult to remove by multiple crystallisations or even by chromatographic separation due to the ester's poor solubility in most polar as well as non-polar solvents.        The conversion of chloromethyl ester 5 to iodomethyl ester 6 suffers from the generation of oxidative degradation impurities. Sulphur compounds 4, 5 and 6 are prone to oxidative dimerisation, and dimer impurities like compounds 11 and 12 were observed at higher temperatures (more than 60° C.) or with longer reaction times. It was observed that such by-products are formed in significant amounts, which are difficult to control/reduce within the limits of stringent pharmacopoeial specifications (EP/USP) even after multiple purifications.        

Compound 11: X=—S—S—[17,17′-(disulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate]
Compound 12: X=—S—S—S—[17,17′-(trisulphanediyldicarbonyl)bis(6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-yl)dipropionate]
The conversion of iodomethyl ester 6 to fluticasone propionate I disclosed in U.S. Pat. No. 4,335,121 suffers from the following limitations:                The reaction takes a long time (72 hours-11 days).        An excess of silver fluoride (10-15 eq) must be used for complete conversion, which causes problems during recovery of the silver fluoride from the waste stream.        Because of the excess of silver fluoride used, a thick black insoluble residue forms, which interferes in the homogeneity of the reaction.        The black suspended metallic particles cannot be eliminated easily by Kieselguhr filtration, where these impurities are carried forward even after multiple filtrations. The black metallic impurities require multiple washings with 2M HCl for complete removal.        In the end, after all the tedious aqueous work up, isolation of the product requires preparative chromatography and two crystallisations to obtain material complying with the pharmacopoeial limits. This chromatographic purification further limits the applicability of this process on a commercial scale.        
According to Israeli patent application IL 109656, fluticasone propionate I was synthesized directly from 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioic acid 4 using a halofluoromethane, for example bromofluoromethane, and phase transfer catalysts, as shown in scheme 2. The disadvantage of this process is the use of halofluoromethanes, such as bromofluoromethane, which are non-eco-friendly reagents known to damage the ozone layer of the atmosphere.

The process described in international patent application WO 2004/001369 involves the following steps depicted in scheme 3.

6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carboxylic acid 7 was converted into the corresponding thiocarbamate 8 using N,N-dimethylthiocarbamoyl chloride in an inert aprotic solvent in the presence of an iodide catalyst and a base. The 17β-N,N-dimethylthiocarbamoyloxycarbonyl compound 8 was treated with an alkali metal carbonate-alcohol system, for example potassium carbonate in methanol, to obtain the alkali metal salt 9 of compound 4 (6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbo-thioate sodium). Alkali metal salt 9 was treated in situ with bromofluoromethane to obtain fluticasone propionate I. Alternatively, compound 4 was isolated by acid treatment and then reacted with bromofluoromethane to obtain fluticasone propionate I. Alternatively still, thiocarbamate 8 was reacted with a hydrosulphide reagent, such as sodium hydrosulphide, and bromofluoromethane to obtain fluticasone propionate I. Hence, this process also uses bromofluoromethane, which raises environmental concerns.
US patent application USSN 2002/0133032 by Abbot Laboratories also discloses the hydrolysis of compound 8 with sodium hydrosulphide to generate alkali metal salt 9, which was then treated in situ with chlorofluoromethane to obtain fluticasone propionate I.
The process disclosed in European patent application EP 1431305 comprises the following steps. Organic amine salts of 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioic acid 10 were prepared with different aliphatic amines in isopropanol as a preferred solvent. The isolated organic amine salt 10 was further reacted with chlorofluoromethane in acetonitrile as a preferred solvent at 50° C. in a closed vessel at a pressure of ˜1.3 bar to afford fluticasone propionate I as shown in scheme 4.

Although the process described in EP 1431305 is capable of producing relatively pure fluticasone propionate I, a drawback associated with this process is the oxidative dimerisation of the sulphur compounds to give dimer impurities 11 and 12, especially under pressure or with long reaction times. Such by-products are formed in significant amounts, which are difficult to control/reduce within the limits of stringent pharmacopoeial specifications even after multiple purifications.
A process disclosed by Farmabios in international patent application WO 2004/052912 used a different approach, shown in scheme 5, for the conversion of organic amine salt 4 to fluticasone propionate I. Amine salt 4 was hydroxymethylated using formaldehyde to give alcohol 13 (S-hydroxymethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxo-androsta-1,4-diene-17β-carbothioate). This intermediate 13 was selectively fluorinated using bis(2-methoxyethyl)aminosulphur trifluoride (DEOXO-FLUOR®), diethylaminosulphur trifluoride (DAST®), or hexafluoropropyldiethylamine (MEC-81®), to obtain fluticasone propionate I.

WO 2004/052912 also discloses a minor modification of the process described in scheme 5. In the modified process, depicted in scheme 6, 17β-N,N-dimethylthiocarbamoyloxy-carbonyl-9β,11β-epoxy-6α-fluoro-17α-propionyloxy-16α-methyl-3-oxo-androsta-1,4-diene 14 was converted to S-hydroxymethyl-9β,11β-epoxy-6α-fluoro-17α-propionyloxy-16α-methyl-3-oxo-androsta-1,4-diene-carbothioate 15. Intermediate 15 was further converted into S-fluoromethyl-9β,11β-epoxy-6α-fluoro-17α-propionyloxy-16α-methyl-3-oxo-androsta-1,4-diene-carbothioate 16 using DAST®. Fluticasone propionate I was then obtained by the opening of the epoxide of compound 16 using hydrofluoric acid. The use of hazardous DAST® as a fluorinating agent and the use of highly corrosive hydrofluoric acid are major disadvantages of this process described in WO 2004/052912.

Thus the prior art processes described above for the synthesis of fluticasone propionate I suffer from various limitations with respect to process parameters, yields, purity and quality, as well as serious environmental issues due to the use of halofluoromethanes. In view of these drawbacks, there is a need for an improved process for the preparation of fluticasone propionate I, which addresses the limitations associated with the prior art processes.
Moreover, thioalkyl derivatives II are very sensitive towards oxidative as well as free radical dimerisation at temperatures of more than 60° C. and by prolonged heating. The present inventors converted iodomethyl ester 6, obtained following the process disclosed in U.S. Pat. No. 4,335,121, into fluticasone propionate I. Even after numerous attempts it was found that the required quality of fluticasone propionate I could not be obtained, unless iodomethyl ester 6 was purified to a certain level before its conversion into fluticasone propionate I. Hence, the purification of iodomethyl ester 6 was essential to obtain fluticasone propionate I of the required quality. However, the purification of this key intermediate, i.e. iodomethyl ester 6, is not disclosed in any of the literature, and in particular not in U.S. Pat. No. 4,335,121.
In addition, iodomethyl ester 6, the dimer impurities and other non-polar related impurities have poor solubility in polar as well as non-polar solvents and therefore the purification of iodomethyl ester 6 by crystallisation or chromatographic separation becomes very tedious and uneconomic. The poor solubility of iodomethyl ester 6, the dimer impurities and other non-polar related impurities also hinders the next step, the synthesis of fluticasone propionate I, where multiple crystallisations as well as chromatographic purifications are required to achieve the pharmacopoeial limits of these impurities (0.3-0.4%).
In view of these problems, there is also a need to develop an improved process for the preparation and purification of the key intermediates, thioalkyl derivatives II, in the preparation of fluticasone propionate I, which addresses the limitations associated with the prior art processes.